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Analyses of Porphyria Caused by Environmental Pollutants : Concerted Reaction and Tempo of Heme and Porphyrin Syntheses

环境污染物引起的卟啉症分析：血红素和卟啉合成的协同反应和节奏

基本信息

批准号：
14208066
负责人：
SHIMIZU Toru
金额：
$ 24.29万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

In eukaryotes, protein synthesis is terminated when cells face an emergency such as a shortage of amino acids, stress to the endoplasmic reticulum, and viral infection. Translation initiation in the red cell is regulated by eukaryotic initiation factor 2a (a-subunit of eukaryotic initiation factor 2 ; eIF2α) kinases or HRI (heme-regulated inhibitor). In the red cell, protein synthesis is terminated when cells face an emergency such as shortage of the heme iron complex. HRI senses and mediates responses to changes in the Fe(II)-protoporphyrin IX (heme) concentration. Under normal conditions when there is sufficient heme, HRI does not phosphorylate eIF2α, but when there is a shortage of heme, it acts to maintain the heme-to-globin ratio at 1:1 by phosphorylating eIF2a, which initiates the termination of protein synthesis. Although HRI is reported to sense the heme concentration in reticulocytes or red blood cells the molecular mechanisms, in particular the role of the N-terminal domain in its oligomerization, kinase function, and heme sensing, have remained elusive. In addition, little is known regarding how heme binds to the catalytic domain and regulates catalysis, the stoichiometry of heme binding, and which residues are axial ligands for the heme iron. In the present study, we attempted to elucidate how the concerted reactions of the heme and protein syntheses are coupled by generating the N-terminal truncated mutants, His mutants, Cys mutants and examining the catalytic function, heme affinities, and heme coordination structures. We also examined effects of environmentally polluted heavy metal cations on the kinase activities of HRI. It was found that NO enhances catalysis of HRI, NO recovers inhibited calysis by heme and bilirubin and heavy metal cations inhibit catalysis. The results obtained will be helpful to understand the molecular mechanism of porphyria caused by environmental pollutants.

在真核生物中，当细胞面临氨基酸短缺、内质网应激和病毒感染等紧急情况时，蛋白质合成就会终止。红细胞中的翻译起始受到真核起始因子 2a（真核起始因子 2 的 a 亚基；eIF2α）激酶或 HRI（血红素调节抑制剂）的调节。在红细胞中，当细胞面临血红素铁复合物短缺等紧急情况时，蛋白质合成就会终止。 HRI 感知并介导对 Fe(II)-原卟啉 IX（血红素）浓度变化的反应。在正常情况下，当血红素充足时，HRI不会磷酸化eIF2α，但当血红素短缺时，它会通过磷酸化eIF2a来维持血红素与珠蛋白的比例为1:1，从而启动蛋白质合成的终止。尽管据报道 HRI 可以感测网织红细胞或红细胞中的血红素浓度，但分子机制，特别是 N 末端结构域在其寡聚化、激酶功能和血红素感测中的作用，仍然难以捉摸。此外，关于血红素如何与催化结构域结合并调节催化作用、血红素结合的化学计量以及哪些残基是血红素铁的轴向配体，人们知之甚少。在本研究中，我们试图通过生成N端截短突变体、His突变体、Cys突变体并检查催化功能、血红素亲和力和血红素配位结构来阐明血红素和蛋白质合成的协同反应是如何耦合的。我们还研究了环境污染的重金属阳离子对 HRI 激酶活性的影响。结果发现NO增强HRI的催化作用，NO恢复血红素和胆红素抑制的催化作用，重金属阳离子抑制催化作用。获得的结果将有助于了解环境污染物引起卟啉症的分子机制。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Investigation of the Relationship between Protein-Protein Interactions

蛋白质-蛋白质相互作用之间关系的研究

DOI：
发表时间：
2005
期刊：
Biochemistry 44(28)
影响因子：
0
作者：
笹倉由貴江他
通讯作者：
笹倉由貴江他

Dual Effects of the Substrate and Pterins on the Kinetics of CO Binding

底物和蝶呤对 CO 结合动力学的双重影响

DOI：
发表时间：
2005
期刊：
Chemistry Letters 34(6)
影响因子：
0
作者：
Bengea;Simona 他
通讯作者：
Simona 他

Importance of valine 567 in substrate recognition and oxidation by neuronal nitric oxide synthase.

DOI：
10.1016/j.jinorgbio.2004.03.015
发表时间：
2004-07
期刊：
Journal of inorganic biochemistry
影响因子：
3.9
作者：
Magali Moreau;Hiroto Takahashi;M. Sari;J. Boucher;I. Sagami;Toru Shimizu;D. Mansuy
通讯作者：
Magali Moreau;Hiroto Takahashi;M. Sari;J. Boucher;I. Sagami;Toru Shimizu;D. Mansuy

Spectroscopic Characterization of the Isolated Heme-bound PAS-B Domain

分离的血红素结合 PAS-B 结构域的光谱表征